The S100 proteins are a major subfamily of EF-hand calcium binding proteins that are distinguished by cell type-specific expression and an unusual prevalence in a variety of disease states. This proposal seeks to address the role of zinc in modulating the functional properties of S100 proteins and will also explore the structural basis for the interaction of S100 proteins to cellular targets. The zinc bound states of three S100 systems will be examined, each having potentially distinct zinc binding modes. The structure and dynamics of four S100-target complexes will be examined in detail. These include complexes with protein ligands and small molecules. These results will link the large amount of experimental data available on S100 proteins and will help reveal the biophysical basis for their biological activity.